Legal Writing Skills for FDA Regulatory Affairs Professionals (sept 2017)

Legal Writing Skills for
Effective FDA Regulatory
Submissions
Robert Michalik, J.D., RAC
RegulatoryPro Consulting
https://www.linkedin.com/in/robertmichalik
September 2017

Legal Writing Skills for Effective FDA Regulatory Submissions
Presenter: Robert Michalik, JD, RAC
About the Presenter …
Robert Michalik J.D, RAC, is a Massachusetts regulatory attorney and
founder of RegulatoryPro Consulting, a firm providing general and
specialized services to the biopharmaceutical and medical device
industries.
I have over 25 years’ experience working in the biopharmaceutical and
medical device industries. I started his career as a research
biochemist (Harvard Medical School / Brigham & Women’s Hospital,
Boston) and later moved into biotechnology specializing in protein
chemistry for several companies spun off from Harvard and MIT in
Cambridge, MA.
After 10 years in the lab helping to develop novel therapeutic biologic
drug products, I entered Suffolk University law school in Boston and
thereafter transitioned into the field of regulatory affairs. I’ve been
working in regulatory affairs profession ever since.

Presentation Outline
Section I: Introduction – Real World Consequences of Ineffective Writing
Section II: Ten Commandments of Effective Legal Writing
Section III: Good Regulatory Writing - IRAC
Section IV: Good Regulatory Writing – Assurance Case
Section V: Good Regulatory Writing – Final Thoughts
“It is the first duty of a hypothesis to be intelligible.”
— Thomas H. Huxley

Presentation Outline: What you will learn …
 Basic communications skills that all successful
attorneys use to win arguments, in legal briefs and
oral presentations.
 How to present both good and poor data in a
persuasive step-by-step manner.
 How to train scientists and engineers to generate
"good" data to support legal, regulatory and quality
claims?
 Tips and secrets to framing an argument that makes
even poor data look good.
 Examples of good writing that can be useful
templates for training and skills development.
 What you should never explicitly state in a quality or
regulatory document?

Response to FDA Request For Additional Data
Assume that FDA rejected your recent NDA as unpersuasive and
requested additional data to support the new drug’s indication as a
treatment for a rare and unmet medical condition, Duchenne muscular
dystrophy.
The addition clinical data generate was good, but it does not clearly
provide the evidence of efficacy and safety to ensure approval. So to
gain FDA approval, you must also submit a ‘benefit risk’ assessment that
will be the driving factor in achieving success.
Additionally your company’s financial resources have been severely
strained and this drug is necessary for corporate survival.
How should you respond?
Section I: Introduction

In fact this is NOT a hypothetical example.
The scenario reflects a real world situation: BioMarin’s NDA

FDA Rejects BioMarin’s Much-Anticipated DMD Drug
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/
peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm473737.pdf
1/14/2016
BioMarin Pharmaceutical Inc said on Thursday
the U.S. Food and Drug Administration had
rejected the company's drug to treat a rare
muscle-wasting disorder.
The drug, Kyndrisa (drisapersen) was expected
to be the first treatment in the United States for
Duchenne muscular dystrophy (DMD) - a
disorder that affects one in 3,600 newborn boys
and causes rapid muscle degeneration.
The rejection comes after a panel of independent
advisers to the FDA indicated that efficacy data
on the drug was not persuasive enough for an
approval.

FDA Advisory Panel Findings & Recommendations
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/
peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm473737.pdf
FDA Rejects BioMarin’s Much-Anticipated DMD Drug

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommitte
e/ucm473737.pdf
FDA Recommendation: Clinical Data Quality

e/ucm473737.pdf
Biomarin’s two
competitors faced
similar challenges
- Approval vs Rejection
Ineffective Regulatory Submissions have real world consequences

e/ucm473737.pdf
Ineffective Regulatory Submissions have real world consequences
Biomarin’s NDA review problems related to more than simply unpersuasive
regulatory writing. FDA specifically cited the clinical efficacy data as a
factor in declining to approve the Kyndrisa (drisapersen) application.
Still, more persuasive writing at all stages and levels in the drug
development process would quite likely enhance the chances of achieving
the overall goal – NDA Approval.
Lets explore writing techniques that might have helped improved the
application.

Follow the Legal Writing
Ten Commandments
These 10 commandments are
fundamental to all good writing!
Particularly when presenting an
argument to federal regulators
Persuasive Legal Arguments:

Legal Writing Ten Commandments *
I. Know Why Your Argument Should Prevail
II. Know Your Standard of Review
III. Know Your Order of Authority
IV. Prepare an Outline to Organize the Structure
of Your Argument
V: Use a Mapping Technique (to track issues)
VI. Be honest With the Agency
VII. Focus on Transitions
VIII. Edit !
IX. Keep It Simple And as Short as Possible.
X. Edit Again ! Section derived, in part, from
• Walbolt, S.; Alle, D.W., Ten Commandments of Writing An Effective Appellate Brief,
• Law Firm of Carlton Fields, LLP

Legal Writing Ten Commandments

Legal Writing 10 Commandments
A. Clearly understand the benefits and risks of your
position
B. What benefit does the reader receive from agreeing
with you?
C. What basic information does the reader need to reach
his/her own conclusions?
D. Could alternative sources of information suffice to
satisfy your reader?
E. What risks or detriments does the reader (i.e., FDA
Reviewer) expose himself to by agreeing?

Legal Writing 10 Commandments
III: Know Your Order of Authority
IV. Prepare an Outline to Organize the Structure of Your Argument
V. Use a Mapping Technique
VI. Focus on Transitions
VII. Edit !
VIII. Keep It Simple And as Short as Possible.
IX. Edit Again !
X. Be honest With the Agency

 How do we address and resolve complex regulatory issues?
• Develop facts based upon validated methods of research
• Know the applicable law
• Address “imperfect data” using the “IRAC” method
 Issue ...... What claim is in dispute? State the issue specifically
 Rule ...... What law or standard directly applies to the issue?
 Break down the rule into its constitutive “elements” / requirements
 Analysis ... What empirical evidence exists to irrefutably prove you
have satisfied each and every element of the law or standard?
 Conclusion .. Clearly state the results of the analysis
If all elements of the rule have been met the issue is no longer in dispute
(i.e., a ‘matter of opinion’) but rather a ‘matter of fact’
For additional information and alternative models see https://en.wikipedia.org/wiki/IRAC

How do we address and resolve complex regulatory issues using the “IRAC” method
For example, assume you’ve been asked to brief the V.P. of Business Development on the
statutory and regulatory requirements for successfully preparing a New Drug Application in
the U.S. .
You of course first review the applicable section of the Food, Drug & Cosmetic Act (FD&C
Act) statute. For this exercise, we will only focus on the clinical requirements obtaining a
license to market your new drug.
Is it possible to clearly and completely identify all legal criteria (elements) that must be
satisfied from simply reviewing the statutory law?

FD&C Act § 505(b)(1) New Drug
Any person may file with the Secretary an application with respect to any drug subject to the provisions of
subsection (a). Such persons shall submit to the Secretary as a part of the application
(A) full reports of investigations which have been made to show whether or not such drug is safe
for use and whether such drug is effective in use;
(B) a full list of the articles used as components of such drug;
(C) a full statement of the composition of such drug;
(D) a full description of the methods used in, and the facilities and controls used for, the
manufacture, processing, and packing of such drug;
(E) such samples of such drug and of the articles used as components thereof as the Secretary may
require;
(F) specimens of the labeling proposed to be used for such drug and
(G) any assessments required under section 505B.
Section 505(b)(1)(A) does not provide adequate granularity with regards to the legal requirements necessary to satisfy this
Congressional mandate. Therefore, you look to the corresponding FDA regulation(s) that expound on the statutory elements of
law. When seeking to comply with FDA law, it is imperative that you always cite the statutory law as the standard of review and
thereafter point to regulatory provisions to demonstrate compliance with the statute.

• Address “imperfect data” using the “IRAC” method
FD&C Act § 505(b)(1) New Drug
Any person may file with the Secretary an application with respect to any drug subject to the provisions of
subsection (a). Such persons shall submit to the Secretary as a part of the application
(A) full reports of investigations which have been made to show whether or not such drug is safe
for use and whether such drug is effective in use; 13

• Using the “IRAC” method, keep breaking down broad ‘elements’ or criteria of the legal provision
until no more ‘granular, and applicable legal source can be found, and then apply the writing
technique to determine if each element of law has been met.
Regulation 21 CFR 314.50(5)(iv) specifically relates to FD&C Act §505(b)(1)(A). Fully satisfy the regulation
and you have satisfied the statutory provision (assuming no other regulation applies)
FDA Regulation, 21 CFR 314.50 (5) Clinical data section
(iv) A description and analysis of any other data or information relevant to an evaluation of the
safety and effectiveness of the drug product obtained or otherwise received by the applicant
from any source, foreign or domestic, including information derived from clinical
investigations, including
 controlled and uncontrolled studies of uses of the drug other than those proposed in
the application,
 commercial marketing experience,
 reports in the scientific literature, and
 unpublished scientific papers.
http://a257.g.akamaitech.net/7/257/2422/26mar20071500/edocket.access.gpo.gov/cfr_2007/aprqtr/21cfr314.50.htm

Simple Example of IRAC: “Case of the Missing Pen”
Lets assume that John, the office manager, becomes irate after losing his
prized engraved pen. He suspects one of the staff members took it from his
office while he was in a meeting.
John approaches his employee, Peter in the break room, and call him a thief
by accusing him of stealing his pen. Peter is embarrassed as there are many
of his co-workers who witnessed this exchange. Peter denies the claim, so
John storms away to speak with the Head of Human Resources about the
matter. The Human Resources Manager calls Peter into her office, questions
him, and shortly thereafter, tells Peter his services are no longer needed in the
company. He has been fired for ‘unspecified reasons’.
A few days later, John’s Administrative Assistant, happens to find the pen
under paperwork stacked on John’s file cabinet. Peter hears of this
development and is furious. He hasn't found a comparable job since being
fired. Peter files a lawsuit against John and the company for defamation.
As his legal representative, how should you build an legal argument to resolve this matter?

Simple Example of IRAC:
The issue is whether or not John’s statement that Peter is a thief constitutes defamation.
Defamation is defined as the issuance of a false statement about another person, which
causes that person to suffer harm.
In this instance, John verbalized or “issued” a statement that Peter was a thief, a derogatory
characterization. The inferential allegation that the pen was stolen was proven to be false
when an unbiased individual, John’s assistant, found the pen in an area under the exclusive
control of John. An investigation into Peter’s employee file revealed that prior to being
fired by his employer, Peter received consistently high praise on his quarterly performance
reviews over the past several years. He was fire within the hour that the allegation was
uttered. Loss of a high wage job has caused Peter harm by lowering his earning power and
quality of life.
Therefore, John’s statement referring to Peter’s purported actions does constitute defamation
and is actionable under law.
Legal Issue
Analysis
-
merging
facts
with
elements
of the
Rule
Applicable Rule /law. Each element comprising the law matters.
Conclusion drawn.
Issue depends upon whether facts exist to
satisfy each of five element of the rule / law

Know your Legal Authority: Basis for your Argument
Below is a list of legal authority – from most powerful to least powerful
1. Statutory law (e.g., Federal Food, Drug and Cosmetic Act),
2. Judicial case law (legal holding in a judicial opinion applicable to your
matter)
3. Regulations (Title 21 Code of Federal Regulations)
4. Prior Agency ruling or interpretation of the statutes, regulations and
case law
5. Agency guidance document
6. Industry standards
7. Internally developed corporate practices & procedures
o (qualified at least, validated preferable)
 Not all sources of law carry the same persuasive weight.
 Powerful legal arguments require citation to “authoritative” law
(statutory, regulatory and judicial case law)

Demystifying Principles of Persuasive Regulatory Writing
Drafting a Regulatory submission:
Lessons we can learn from the
“Three Little Pigs”

Three Approaches toward preparing a regulatory submission
and “Assurance Case” arguments.
FDA’s Data Expectations that Support Safety and
Effectiveness Claims
AdequateWeak Solid

#1 Primary arguments are missing key data or the data
quality of is poor; little technical EVIDENCE to support
claims, for example in reports:
•Unclear purpose or acceptance criteria
•Unclear scope
•Poor analysis of results and/or follow-through in the
explanation
#2 product risks were not fully identified, analyzed or
sufficiently mitigated.
#3 Main safety claims do not clearly relate to the
underlying claims (sub-issues) nor are they supported by
facts. Key issues are not properly resolved using IRAC
approach.
#4 Poor structure, sloppy presentation
The “Straw house” Regulatory submission –
Failure to follow the law, missing data and/or poorly structured
argument

#1 Quality of technical EVIDENCE is fairly good but the
data is poorly analyzed so ‘information’ gleaned doesn’t
support claims in a clear, compelling argument.
• IRAC of primary issues, but no IRAC of
secondary or tertiary issues.
• Generally clear purpose and acceptance criteria
• No clear relationship among product
requirements, risks and mitigation efforts.
Review is left to “connect the dots” regarding the
evaluation of residual Risks vs. Benefits to Pt.
#2 Key device risks were identified, but not clear whether
each was adequately mitigated.
#4 Better structure, but inconsistent presentation
The “Stick house” Regulatory Submission -
Follows FDA law and is modeled after FDA recommended “Guidance for
Industry”, but the central clinical or scientific claims are not sufficiently
supported by data.
Issue
Rule
Analysis
Conclusion

#1 High quality of technical EVIDENCE to support
argument, for example in reports:
• Clear purpose, quantifiable acceptance criteria
• Clear scope
• Thorough fact-based analysis of test results that
are cogently related to each element of tech
standard or regulatory requirement.
#2 All critical device risks were identified and specifically
addressed in mitigation effort.
#3 Main safety claims seamlessly integrated into
underlying claims (sub-issues) and supported by
empirical data and ascertainable facts.
#4 Submission structure modeled after FDA Guidance
template.
The “Brick house” Regulatory Submission -
Structured arguments satisfy FDA law, modeled after FDA Guidance for
Industry and incorporates characteristics of a compelling “IRAC” Argument

FDA Review Process:
FDA Reviewer trying to blow down our safety and effectiveness claims.
FDA’s objectives:
 Find weaknesses in our submission by looking for spurious arguments;
 For biopharmaceutical product review, FDA Office of Drug Evaluation will challenge the Sponsor’s claims. Does
the investigational drug satisfy legal criteria mandated in the FD&C Act? Does the benefit from using the drug
outweigh known or probable risks? Is it reasonably safe and effective for its indication for use?
 For medical device review, FDA Office of Device Evaluation will challenge the Sponsor’s claims. Is the proposed
device ‘substantially equivalent’ to a predicate device? Is it reasonably safe and effective for its intended use?
Solid
“Brick wall”
Regulatory
argument

FDA has endorsed the “IRAC” approach, but identifies the steps in the process as
“Assurance Case” which involves three parts:
1) Claims, 2) Evidence & 3) Analysis
The terminology is different but the regulatory writing objectives are the same. Provide
empirical evidence that the elements of a claims can be supported by valid data
The BRICK represents
the irrefutable conclusion
of a claim
(via IRAC issue resolution)
The MORTAR between the
bricks represents your inter-
issue analysis that connects
subissues together in a
seamless, logical manner.
The completed wall
represents the final
regulatory submission. All
issues resolved and sub-
claims and claims meet legal
requirements.
Refer to FDA Guidance: 510(k) Infusion Pumps & Assurance Case

Persuasive ‘Assurance Case’ to build a Solid regulatory argument:
Step 1: Resolve Issues using the ‘Assurance Case’ Method
“Create strong bricks to build your AC”
Three main elements of an assurance case are:
Claim: Statement about a property of the system or a subsystem
(Also referred to as an “Issue” in dispute)
Evidence: Information that demonstrates the validity of the claim.
Evidence requires facts (e.g., based on observations or established
scientific principles), analysis, research conclusions, test data, or expert opinions.
Argument: Links the evidence to the claim.
Arguments can be deterministic, probabilistic, or qualitative.
The argument will describe what is being proved or established (i.e., the claim(s)), identify the
items of evidence you are appealing to, and the reasoning (inference, rationale) that the evidence
is adequate to satisfy the claim. Arguments may also introduce sub-claims or assumptions which
require further exposition, as the preceding examples illustrate.

Assurance Case & Good Legal Analysis:
Similar Approaches toward Claim / Issue Resolution
http://west.thomson.com/pdf/perspec/how1299.pdf
Legal Reasoning (IRAC - Issue Resolution Model)
All legal reasoning follows one path. No legal argument can be accepted or
rejected without all of the following pieces
1) Issue - What specifically is being debated?
2) Rule - What legal or technical rule governs this issue?
3) Facts - What are the indisputable facts relevant to this Rule?
(Note: a disputable fact actually creates an issue of veracity)
4) Analysis - Apply indisputable facts to each element of a rule
5) Conclusion - Having applied the rule to the facts, what's the outcome?

Assurance Case & Good Legal Analysis:
Similar Approaches toward Issue Resolution
http://west.thomson.com/pdf/perspec/how1299.pdf
How to present
“Issue” statements

How to assemble the Assurance Case:
Once “minor issues” have been concisely addressed, close your discussion regarding
the elements of the “major issue”
The “mortar” that connects your “resolved issues” is your transitional phrases and
logical discussion of the overall issues.
Persuasive insights that relate minor claim conclusions yield knowledge that FDA
cannot dispute.

Building the Safety Case and Claims
• Assembly information from
the Risk Management and
Design Control files
• Focus on hazards and
mitigated efforts
• Key is to generate
“evidence” (irrefutable
facts) that support safety
claim arguments.

https://info.legalsolutions.thomsonreuters.com/pdf/perspec/1999-fall/1999-fall-11.pdf
 Address fairly any other reasonable
position (counter-argument) that might
be advanced by the opposing party
 Don’t ignore or conceal any uncertainties,
inconsistencies, ambiguities or conflicts in the law
or scientific basis of your argument.
Understand Both Sides of the Regulatory and Technical Issues
 Explicitly identify each KEY weakness and then resolve it with
logic.

Building your Regulatory Argument:
Compile all resolved sub-issues that Verify and Validate the main Claims
Integrate the resolved major claims and issues to meet core
FDA regulatory & statutory requirements.
If each “brick” (resolved claim) is objectively integrated with the other related
claims (bricks) using persuasive arguments (“mortar”).
When all legal elements have been addressed adequately, the final “wall”
(argument that product is reasonably safe & effective) cannot be pushed down
during FDA review.

A solid foundation A weak foundation
Submission with missing or weak
Assurance case argument leads to …
Submission with strong Assurance
case argument leads to …

1. Know the law and regulatory requirements related to medical
devices
2. Frame your claims in terms that reflect FDA requirements
3. Rigorously apply the Assurance Case model and IRAC issue
resolution approach to effectively draw irrefutable conclusions about
discrete claims
4. Persuasive tell a narrative story that integrate ‘conclusions’ into a
larger whole (major claim such as a device is reasonably safe)
5. Compile all major claims into a submission that follows the FDA’s
recommended format and is ‘clean’, error-free and easy to navigate.
6. State the ultimate claim (“device is SE and reasonably safe &
effective”) and ensure the overall submission “nests” the sub-claims
and minor claims in a cogent fashion. “The onion approach”

Know your Reviewer: Final thoughts
Self-Interest Persuasion Principle
 Demonstrate to the other party why it is in their best interest to accept your
proposal.
 Carefully listen to their needs and desires, then tailor your argument to focus on
how your approach will help them achieve their needs and fears.
 Ask questions to determine what the other party is seeking or holds as
priorities. Then make sure that your offer or counter-offer addresses those
priorities.
 Don’t necessarily give FDA everything they ask for, but rather show them how
their goal is still met through what you offer.
 The principle of self-interest states that people are more likely to do something
if they perceive it to be in their best interest.

When drafting a regulatory submission and responding to an
FDA Reviewer’s comments, remember “Getting to Yes”

Bibliography
• Graydon, P., Knight, J., and Strunk, E., “Assurance Based Development of Critical Systems,”
Proc. of 37th Annual International Conference on Dependable Systems and Networks, Edinburgh,
U.K., 2007;
• Kelly, T., Arguing Safety— A Systematic Approach to Managing Safety Cases, Ph.D.
Dissertation, University of York, U.K., 1998;
• Kelly, T., “Reviewing Assurance Arguments- A Step-by-Step Approach,” Proc. of Workshop
on Assurance Cases for Security- The Metrics Challenge, Dependable Systems and Networks,
July 2007;
• Kelly, T. and McDermid, J., “Safety Case Patterns– Reusing Successful Arguments,” Proc. of
IEE Colloquium on Understanding Patterns and Their Application to System Engineering,
London, Apr. 1998;
• Weinstock, C.B. and Goodenough, J.B.,“Towards an Assurance Case Practicefor Medical
Devices,” Carnegie Mellon Software Engineering Institute, October 2009.
• Phatak, O., Learn How to Write a Valid Hypothesis for Your Research Paper, Buzzle.com 26Sept
2016 https://www.buzzle.com/articles/how-to-write-a-hypothesis.html
• Deshpande, N., Know the Difference Between Null and Alternative Hypothesis, Buzzle.com,
14Nov2016 https://www.buzzle.com/articles/difference-between-null-and-alternative-hypothesis.html
• Solomon, D.; Identifying and Understanding Standards of Review, Georgetown Law School, 2013

Questions?
Copyright © 2017 by RJ MIchalik. Limited rights reserved. This document or any portion thereof may be reproduced or used in any manner expressly
permitted by U.S. copyright law whatsoever without the express written permission of the author Provide attribution of the material use is given to the
author as described herein.

Upcoming webinars by :
How to Avoid an FDA Warning Letter: Legal & Regulatory Strategies
you Need to Know
Wednesday, June 7, 2017
10:00 AM PDT | 01:00 PM EDT,
90 Minutes
Legal Writing Skills used in Preparing Premarketing Drug or Medical
Device Applications
Thursday, June 29, 2017
10:00 AM PDT | 01:00 PM EDT,
90 Minutes

Legal Writing Skills for FDA Regulatory Affairs Professionals (sept 2017)

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